IAJPS 2018, 05 (03), 1525-1531 P.

Veera Lakshmi et al ISSN 2349-7750

CODEN [USA]: IAJPBB ISSN: 2349-7750

INDO AMERICAN JOURNAL OF

PHARMACEUTICAL SCIENCES
http://doi.org/10.5281/zenodo.1205060

Available online at: http://www.iajps.com Research Article

PREPARATION AND EVALUATION OF STARCH ACETATE-

GLICLAZIDE MICROPARTICULATE DRUG DELIVERY
SYSTEMS FOR ORAL CONTROLLED RELEASE: INVITRO
STUDIES
P.Veera Lakshmi1, K. P. R Chowdary2, A. Prameela Rani3, S, V. U. M.Prasad4
1
Ph.D Scholar, School of Pharmacy, JNTUK Kakinada -533003 A.P.
2
Research Director, Vikas Institute of Pharmaceutical Sciences, Rajahmundry-533102 A.P
3
University College of Pharmaceutical Sciences, ANU, Guntur
4
Programme Director, School of Pharmacy, JNTUK, Kakinada
Abstract:
Recently much emphasis is being laid on the development of microparticulate DDS in preference to single unit systems because of their potential
benefits such as increased bioavailability, reduced risk of systemic toxicity, reduced risk of local irritation and predictable gastric emptying. The
objective of the present study is to prepare and characterize starch acetate and to evaluate its application in the prepara tion of microparticulate
drug delivery systems for oral controlled release of gliclazide. Starch acetate was prepared by acetylation of potato starch with acetic
anhydride. The prepared starch acetate was characterized and evaluated.
Starch acetate with a degree of substitution 2.75 could be prepared by acetylation of potato starch with acetic anhydride. The starch acetate
prepared was feely soluble in chloroform and insoluble in several aqueous fluids and organic solvents. Chloroform could be used as solvent for
starch acetate in the preparation of microparticles, microcapsules and in film coating Spherical starch acetate- Gliclazide microparticles could
be prepared by the emulsification-solvent evaporation method. The method is industrially feasible as it involves emulsification and removal of the
solvent, which can be controlled precisely. The emulsification solvent evaporation method was reproducible with regard to size and size
distribution of the microparticles. About 65-70% of microparticles in each batch were in the size range 35/50 mesh (398.5µm) Encapsulation
efficiency was in the range 96.0-99.3 % in the preparation of microparticles.
Gliclazide release from the starch acetate microparticles was slow and spread over longer periods of time. The drug release d epended on the
proportion of core:coat in the microparticles. A good linear relationship (R² = 0.826 ) between percent coat and release rate (k o) was observed.
The relationship could be expressed by the linear equation, y = 12.18-0.173x where x is percent coat and y is release rate (ko). Gliclazide release
from the starch acetate microparticles was by non fickian (anomalous) diffusion. Formulation F2 prepared using a Core :coat ratio of 8:2 gave
slow, controlled and complete release(100%) of Gliclazide over 12 hours. As such formulation F2 is considered as a promising microparticulate
DDS for oral control release of Gliclazide over 12 hours for b.i.d administration
Key words: Multiparticulate drug delivery systems, Starch acetate, Gliclazide, Oral controlled release
Corresponding author:
Prof. K.P.R. Chowdary QR code
Research Director,
Vikas Institute of Pharmaceutical Sciences,
Rajahmundry-533102
Mobile No: 09866283578
E-mail: prof.kprchowdary@rediffmail.com
Please cite this article in press P.Veera Lakshmi et al, Preparation and Evaluation of Starch Acetate-Gliclazide
Microparticulate Drug Delivery Systems for Oral Controlled Release: In vitro Studies, Indo Am. J. P. Sci, 2018;
05(03).

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 IAJPS 2018, 05 (03), 1525-1531
INTRODUCTION:
The design of microparticulate drug delivery systems
is an efficient technique to provide the sustained &
controlled delivery of drugs over long periods of
time. Microparticulate drug delivery systems [1]
consist of small particles of solids or small droplets
of liquids surrounded by walls of natural & synthetic
polymer films of varying thickness & degree of
permeability acting as a release rate controlling
substance & have a diameter upto the range of
0.1µm-200µm. Microparticulate dosage forms [2] are
pharmaceutical formulations in which the active
substance is present as a number of small
independent subunits. To deliver the recommended
total dose, these subunits are filled into capsules,
encapsulated or compressed into a tablet.
Microparticulate drug delivery systems contain
discrete particles that make up a multiple-unit
system. They provide many advantages over single-
unit systems because of their small size.
Multiparticulates are less dependent on gastric empty
time, resulting in less inter and intra-subject
variability in gastrointestinal transit time. They are
also better distributed and less likely to cause local
irritation [3]. Recently much emphasis is being laid
on the development of microparticulate dosage forms
in preference to single unit systems because of their
potential benefits such as increased bioavailability,
reduced risk of systemic toxicity, reduced risk of
local irritation and predictable gastric emptying [4].
Design of microparticulate drug delivery systems
requires a suitable polymer to serve the intended
purpose. Several polymers such as benzyl cellulose,
cellulose nitrate, cellulose acetate, epoxy resin, ethyl
cellulose, polyethylene, polymethyl methacrylate,
polystyrene, polyvinyl acetate, Eudragit S-100,
chitosan have been used in the design of
microparticulate drug delivery systems [5,6]. In the
present investigation Starch acetate, a new modified
starch was tried for the preparation of
microparticulate drug delivery systems of gliclazide
for oral controlled release. Modified starches have
been used [7,8] for various pharmaceutical purposes
such as fillers, superdisintegrants and matrix formers
in capsules and tablet formulations. One of the
important modification of starch is acetylated starch.
Starch acetate is reported [9,10] to have excellent
bond forming ability and suitable for coating and
controlled release applications. Much of the literature
on starch acetate and its industrial applications are
patented.
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P.Veera Lakshmi et al ISSN 2349-7750
The objective of the present study is to prepare and
characterize starch acetate and to evaluate its
application in the preparation of microparticulate
drug delivery systems for oral controlled release of
gliclazide. Gliclazide is a potential second
generation, short-acting sulfonylurea oral
hypoglycaemic agent widely used for the treatment of
non-insulin-dependent diabetes mellitus [11]. In
general, rapid gastrointestinal absorption is required
for oral hypoglycaemic drugs in order to prevent a
sudden increase in blood glucose level after food
intake in patients with diabetes mellitus. However,
the absorption rate of gliclazide from the
gastrointestinal tract is slow and varied among
subjects. Slow absorption of a drug usually originates
from either poor dissolution of the drug from the
formulation or poor permeability of the drug across
the gastrointestinal membrane [12] .The dose of
Gliclazide is 40-80mg as conventional tablets and
60mg as sustained release tablets. The conventional
tablets are to be taken 2-3 times a day to maintain
normal plasma glucose levels. Sustained release
formulations offer better patient complains by
reducing the frequency of dosage administrations and
also provide continuous effect. The reported [5,6]
methods for the preparation of microparticulate drug
delivery systems include emulsion–solvent
evaporation (o/w, w/o, w/o/w), phase separation (non
solvent addition and solvent partitioning), interfacial
polymerization, spray drying, emulsion extraction
process, jet milling technique, fluidization & solvent
precipitation method, and pan coating. In the present
study emulsification-solvent evaporation method [13-
20] was tried for the preparation of starch acetate-
gliclazide microparticles.
MATERIALS AND METHODS:
Materials:
Gliclazide was a gift sample from M/s Micro Labs
Limited, Pondicherry. Potato starch (SD Fine
chemicals), acetic anhydride (Qualigens), sodium
hydroxide (Qualigens) and chloroform (Qualigens)
were procured from commercial sources. All other
materials used were of pharmacopoeial grade.
Methods:
Estimation of Gliclazide:
An UV Spectrophotometric method based on the
measurement of absorbance at 227 nm in phosphate
buffer of pH 7.4 was used for the estimation of
gliclazide. The method was validated for linearity,
accuracy, precision and interference by the
excipients. The method obeyed Beer’s law in the
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 IAJPS 2018, 05 (03), 1525-1531
concentration range of 1 – 10 µg/ ml. When a
standard drug solution was repeatedly assayed (n=6),
the relative error and coefficient of variance (RSD)
were found to be 0.80% and 1.2% respectively. No
interference by the excipients used in the study was
observed.
Preparation of Starch Acetate:
Potato starch (20 parts), acetic anhydride (80 parts)
and sodium hydroxide 50 % solution (40 parts) were
mixed and refluxed for 5 h at 160 ºC. The reaction
mixture was added to cold water to precipitate the
starch acetate formed. The product was collected by
vacuum filtration, washed repeatedly with water and
dried at 80 ºC for 4 h.
Characterization of Starch Acetate:
The prepared starch acetate was characterized by
determining the extent of acetylation and degree of
substitution and by IR spectra. Solubility
characteristics (qualitative) were also tested in
various solvents.
Determination of Degree of Substitution:
A powdered starch acetate sample (1.0 g) was placed
in a 250 mL flask and 50 mL of 75 % ethanol in
distilled water solution were added. The mixture was
agitated, warmed to 50 ºC, held at that temperature
for 0.5 h and cooled, then 40 mL of 0.5 N potassium
hydroxide were added. The mixture was then allowed
to stand for 72 h with occasional mixing. The excess
alkali was back titrated with standard 0.5 N
hydrochloric acid using phenolphthalein as indicator.
A blank was titrated in the same way using an
original sample of starch. The acetylation level was
calculated using the equation, acetylation (%) = [mL
(blank) – mL (sample) × normality of acid × 0.043 ×
100]/[ weight of sample in g (dry basis)]. The degree
of substitution was calculated using the equation,
degree of substitution = [162 × acetylation %]/[4300
× (42 × acetylation %)].
IR Spectra:
IR spectra were recorded on Perkin-Elmer
spectrometer, 1000 Model, using chloroform as
solvent.
Preparation of Starch Acetate-Gliclazide
Microparticulate DDS:
An emulsification solvent evaporation method was
tried for preparation of starch acetate- gliclazide
microparticulate DDS. Starch acetate (0.2 g) was
dissolved in chloroform (10mL) to form a
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P.Veera Lakshmi et al ISSN 2349-7750
homogeneous solution. Core material, gliclazide (0.8
g) was added to the polymer (starch acetate) solution
(5 ml) and mixed thoroughly. The resulting mixture
was then added in a thin stream to 200 ml of an
aqueous mucilage of sodium CMC (0.5 % w/v)
contained in a 450 ml beaker while stirring at 1000
rpm to emulsify the added dispersion as fine droplets.
A Remi medium duty stirrer with speed meter (model
RQT 124) was used for stirring. The solvent,
chloroform was then removed by continuous stirring
at room temperature (28 ºC) for 3 h to produce
spherical microparticles. The microparticles were
collected by vacuum filtration and washed repeatedly
with water. The product was then air dried to obtain
discrete microparticles. Different proportions of
core:coat namely 9:1 (F1), 8:2 (F2), 7:3 (F3) and
6:4(F4) were used to prepare microparticles with
varying amount of coat polymer.
Estimation of Drug Content and Encapsulation
Efficiency:
Four samples of 100mg each were taken from each
batch of microparticles prepared and assayed for
gliclazide content at 227nm .Encapsulation efficiency
was estimated using the equation,
Encapsulation efficiency (%)==[Estimated drug
content,%/Theoritical drug content%]X100
Size Analysis:
For the size distribution analysis, different fractions
in a batch were separated by sieving using a range of
standard sieves. The amounts retained on different
sieves were weighed.
Drug Release Study:
Release of gliclazide from the microparticles of size
20/30 and 30/50 mesh was studied in phosphate
buffer of pH 7.4 (900 ml) using an 8 station
dissolution rate test apparatus (model Disso-2000,
M/s Lab. India) with a paddle stirrer( Apparatus 2) at
50 rpm. A temperature of 37º ± 1 ºC was maintained
through out the experiment. A sample of
microparticles equivalent to 60 mg of gliclazide was
used in each test. Samples (5 ml) were withdrawn
through a filter (0.45 µ) at different time intervals
over 12 h and were assayed at 227nm for gliclazide
content. The sample (5 ml) taken at each sampling
time was replaced with drug free dissolution fluid
and a suitable correction was applied for the amount
of drug lost in sampling for the estimation of amount
of drug released at various times. Each drug release
experiment was conducted in triplicate (n=3).
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Analysis of Release Data: solution in chloroform containing the dispersed drug

Drug release data were analyzed as per zero order,
first order, Higuchi [21] equation and Korsmeyer-
Peppas[22] equation models to asses the release
kinetics and mechanism.
RESULTS AND DISCUSSION:
Starch acetate was prepared by acetylation of potato
starch with acetic anhydride .Starch acetate prepared
was found to be a white crystalline powder. The
percent acetylation was 28.38 % and the degree of
substitution was 2.75. The IR spectrum of starch
acetate showed the acetyl carbonyl stretching at 1749
cm-1, which was absent in the IR spectrum of potato
starch, indicating the acetylation of the native starch.
The starch acetate prepared was insoluble in water,
aqueous buffers of pH 1.2 and 7.4, methanol,
petroleum ether, dichloromethane and cyclohexane. It
is freely soluble in chloroform. Hence chloroform
was used as the solvent for starch acetate in the
preparation of microparticulate DDS.
An emulsification - solvent evaporation method was
used for the preparation of micropaticles of starch
acetate-gliclazide. The method involves
emulsification of the polymer (starch acetate)
particles in an immiscible liquid medium (0.5 % w/v
solution of sodium CMC) as microdroplets, followed
by removal of the solvent, chloroform by continuous
stirring to form rigid microparticles. The
microparticles were collected by vacuum filtration
and washed repeatedly with water. The product was
then air dried to obtain discrete microparticles. The
microparticles were found to be discrete, spherical
and free flowing. The sizes could be separated
readily by sieving and a more uniform size range of
microparticles could easily be obtained. The sieve
analysis of different batches of microparticles
prepared indicated that a large proportion,65-70%, in
each batch were in the size range of 35/50
mesh(398.5µm).The reproducibility of the method
with regard to size distribution of the microparticles
was evaluated by preparing three batches of
microparticles under identical conditions in each
case. Size analysis indicated that about 65-70% of
the microparticles are in the size range 35/50 mesh in
all the batches. Microparticles of the size (398.5µm)
were selected for further evaluation.
The physical characterstics of the microparticulate
DDS prepared are given in Table 1.

Table 1: Physical Characterstics of the Microparticulate DDS Prepared

DDS Mesh Size Mean size Core:Coat Gliclazide Encapsu Percent
(μm) ratio content(%) lation Coat
(x̅±sd) efficiency Polymer
(%)
F1 20/35 670 9:1 87.2±1.6 96.9 12.8
35/50 398.5 9:1 86.4±1.4 96.0 13.6
F2 20/35 670 8:2 79.2±1.2 993 20.8
35/50 398.5 8:2 78.6±1.4 98.3 21.4
F3 20/35 670 7:3 69.5±1.3 99.3 30.5
35/50 398.5 7:3 68.4±1.4 97.7 31.6
F4 20/35 670 6:4 58.2±1.2 97.0 41.8
35/50 398.5 6:4 58.4±1.1 97.3 41.6

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 IAJPS 2018, 05 (03), 1525-1531 P.Veera Lakshmi et al ISSN 2349-7750

Fig.1: Gliclazide Release Profiles of Various Microparticulate DDS Prepared

Low coefficient of variation (cv) in percent drug
content (< 2.0 %) indicated uniformity of drug
content in each batch of microparticles. The
encapsulation efficiency was in the range 96.0-99.3
%. Drug content of the microparticles was found to
be the same in the two sizes, 20/35, 35/50 mesh. A t-
test of significance indicated that the difference in the
drug content of the two sizes in each case is not
significant (P>0.05).
Gliclazide release from the various microparticles of
size 3 5/50 was studied in phosphate buffer pH 7.4.
The drug release profiles are shown in Fig.1.the
release data data were analyzed as per Zero order,
First order, Higuchi[21] equation and Korsmeyer-
Peppas[22] equation models to asses the release
kinetics and mechanism. The kinetic parameters (r 2
values, rate constants and n values) in the analysis of
release data as per various kinetic models are given in
table 2.
Gliclazize release from all the starch acetae
microparticles tested was slow and spred over longer
periods of time.The release depended on proportion
of core and coat in the microparticles.As the coat
proportion was increased the release rate was
decresed. A good linear relationship (R² = 0.826 )
between percent coat and release rate (ko) was
observed as shown in Fig2.

Fig.2: Relationship between Percent Coat and Release Rate (K0)

of Microparticulate DDS (Size 398.5μm)
The relationship could be expressed by the linear equation, y = 12.18-0.173x where x is percent coat and y is release
rate (ko).

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 IAJPS 2018, 05 (03), 1525-1531 P.Veera Lakshmi et al ISSN 2349-7750

Table 2: Kinetic Parameters (R2 Values, Rate Constants and n values) in the Analysis of Release Data as per
Various Kinetic Models
DDS Zero order First order Higuchi Korsemeyer Peppas
K0 R2 R2 K1 R2 n R2
F1 10.8 0.8502 0.9800 0.4604 0.9898 0.454 0.9950

F2 7.4 0.9397 0.9300 0.3220 0.9663 0.471 0.9979

F3 6.2 0.9522 0.9410 0.1612 0.9195 0.454 0.9886

F4 5.6 0.9765 0.9853 0.1150 0.9317 0.542 0.9965

A comparision of R² values in various models
revealed that the R² value was higher in the case of
korsmeyer peppas model in all the cases. As such the
release data of all the microparticles tested obeyed
korsmeyer peppas equation model which indicates
that the drug release from the microparticles was by
diffusion mechanism. The release exponent (n) in
korsmeyer peppas equation model was in the range
0.454-0.542 in all the cases indicating that the drug
release from the microparticles was by non- fickian
(anomalous) diffusion.
The results of the present study, thus, indicated that
starch acetate- Gliclazide microparticles could be
prepared by emulsification solvent evaporation
method using chloroform as solvent for starch
acetate. These microparticles could be used for oral
control release of Gliclazide. Formulation F2
prepared using a Core :coat ratio of 8:2 gave slow,
controlled and complete release(100%) of Gliclazide
over 12 hours. As such formulation F2 is considered
as a promising microparticulate DDS for oral control
release of Gliclazide over 12 hours for b.i.d
administration.
CONCLUSIONS:
1. Starch acetate with a degree of substitution 2.75
could be prepared by acetylation of potato starch
with acetic anhydride.
2. The starch acetate prepared was feely soluble in
chloroform and insoluble in several aqueous
fluids and organic solvents.
3. Chloroform could be used as solvent for starch
acetate in the preparation of microparticles,
microcapsules and in film coating
4. Spherical starch acetate- Gliclazide
microparticles could be prepared by the
emulsification-solvent evaporation method. The
method is industrially feasible as it involves
emulsification and removal of the solvent, which
can be controlled precisely.
5. The emulsification solvent evaporation method
was reproducible with regard to size and size
distribution of the microparticles. About 65-70%
of microparticles in each batch were in the size
range 35/50 mesh(398.5µm)
6. Encapsulation efficiency was in the range 96.0-
99.3 % in the preparation of microparticles.
7. Gliclazide release from the starch acetate
microparticles was slow and spread over longer
periods of time. The drug release depended on
the proportion of core:coat in the microparticles.
8. A good linear relationship (R² = 0.826 ) between
percent coat and release rate (ko) was observed.
The relationship could be expressed by the linear
equation, y = 12.18-0.173x where x is percent
coat and y is release rate (ko).
9. Gliclazide release from the starch acetate
microparticles was by non fickian (anomalous)
diffusion.
10. Formulation F2 prepared using a Core :coat
ratio of 8:2 gave slow, controlled and complete
release(100%) of Gliclazide over 12 hours. As
such formulation F2 is considered as a promising
microparticulate DDS for oral control release of
Gliclazide over 12 hours for b.i.d administration
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